Diminished PDE4D7 Expression is Associated with Treatment-Resistant, Lethal Prostate Cancer and Manifests with Impaired Androgen Response, Neuroendocrine Differentiation and Alterations in DNA Repair

Abstract Androgen signalling remains the seminal therapeutic approach for management of advanced prostate cancer. However, most tumours eventually shift towards an aggressive phenotype, characterised by androgen-independence and treatment resistance. The cyclic adenosine monophosphate (cAMP) pathway plays a crucial role in regulating various cellular processes, with the phosphodiesterase PDE4D7 being a vital modulator of cAMP signalling in prostate cancer cells. Our study provides evidence that loss of PDE4D7 expression represents a pivotal switch driving the transition from an androgen-sensitive state to hormone unresponsiveness and neuroendocrine differentiation. Additionally, we demonstrate that PDE4D7 loss results affects DNA repair pathways, conferring resistance to poly ADP ribose polymerase (PARP) inhibitors. Reinstating PDE4D7 expression sensitises prostate cancer cells to anti-androgens, DNA damage response inhibitors, and cytotoxic therapies. These findings provide significant insight into the regulatory role of PDE4D7 in the development of lethal prostate cancer and the potential of its modulation as a novel therapeutic strategy.